This proposal aims to renew our established Alzheimer's Disease Research Center (ADRC) at the University of California at Irvine (UCI). The ADRC will focus on the basic cellular and molecular mechanisms of brain aging and Alzheimer's disease (AD), seek to identify mechanisms of early pathogenic change and relate these mechanisms to cognitive and behavioral functions. Building upon the existing UCI Institute for Brain Aging and Dementia, a strong group of investigators including many new faculty, and continuing commitments by UCI, the ADRC will offer an opportunity to link pioneering basic research into early cellular and molecular mechanisms of AD to clinical applications, and apply clinical insights to basic research. The ADRC will bring several themes to AD research: first are basic and clinical studies on brain plasticity and compensation - particularly learning and memory, second, a cutting-edge basic science perspective on the mechanisms of neurodegeneration with a commitment to link basic and clinical studies, and third, a new initiative to study clinical, neuropsychological and neuropathological characteristics of the oldest-old (90+ year-olds). The three ADRC Projects are directed at investigating mechanisms hypothesized to contribute to early aging and AD progression. Project 1 focuses on neural correlates of episodic memory in subjects including the oldest-old using cognitive tasks and functional brain imaging. Projects 2 and 3 focus on cellular and molecular mechanisms. Many investigators recognize two candidate mechanisms associated with the pathogenesis of AD: 1) mitochondria! Dysfunction and oxidative damage 2) beta-amyloid accumulation, and neurofibrillary tangle formation. Accordingly, one Project is directed at understanding mitochondria! variations and somatic mutations while the other is devoted to the application of immunotherapy to reduce tau aggregates and tangles. As its long-term goal, the UCI-ADRC will strive to incorporate the latest in modern neurosciences and cognitive neurosciences to elucidate the nature of molecular and cellular dysfunction mediated behavioral changes. The proposed ADRC infrastructure will support the Projects and over 30 other faculty investigators in the ADRC.